Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis
Takuwa Yasuda, … , Shigeharu Wakana, Hisahiro Yoshida
Takuwa Yasuda, … , Shigeharu Wakana, Hisahiro Yoshida
Published April 25, 2016
Citation Information: J Clin Invest. 2016;126(6):2064-2076. https://doi.org/10.1172/JCI82887.
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Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis

Abstract

Skin homeostasis is maintained by the continuous proliferation and differentiation of epidermal cells. The skin forms a strong but flexible barrier against microorganisms as well as physical and chemical insults; however, the physiological mechanisms that maintain this barrier are not fully understood. Here, we have described a mutant mouse that spontaneously develops pruritic dermatitis as the result of an initial defect in skin homeostasis that is followed by induction of a Th2-biased immune response. These mice harbor a mutation that results in a single aa substitution in the JAK1 tyrosine kinase that results in hyperactivation, thereby leading to skin serine protease overexpression and disruption of skin barrier function. Accordingly, treatment with an ointment to maintain normal skin barrier function protected mutant mice from dermatitis onset. Pharmacological inhibition of JAK1 also delayed disease onset. Together, these findings indicate that JAK1-mediated signaling cascades in skin regulate the expression of proteases associated with the maintenance of skin barrier function and demonstrate that perturbation of these pathways can lead to the development of spontaneous pruritic dermatitis.

Authors

Takuwa Yasuda, Toshiyuki Fukada, Keigo Nishida, Manabu Nakayama, Masashi Matsuda, Ikuo Miura, Teruki Dainichi, Shinji Fukuda, Kenji Kabashima, Shinji Nakaoka, Bum-Ho Bin, Masato Kubo, Hiroshi Ohno, Takanori Hasegawa, Osamu Ohara, Haruhiko Koseki, Shigeharu Wakana, Hisahiro Yoshida

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Figure 7

Overexpression of serine proteases in Spade-mutant skin and their role in dermatitis development.

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Overexpression of serine proteases in Spade-mutant skin and their role i...
(A) Changes in mRNA levels of serine proteases determined by microarray analysis. Each bar depicts the ratio of mRNA expression level in the ear skin of Jak1Spade/Spade mice to that in WT mice at 2, 4, and 6 weeks of age. (B and C) mRNA expression levels of Klk6 (B) and marapsin (C) in skin from 6-week-old Jak1Spade/Spade and WT mice determined by qRT-PCR. Error bars represent the mean ± SD of 6 mice per group. ***P < 0.001, by 2-tailed Student’s t test. (D and E) Luciferase assay for Klk6 (D) and marapsin (E) promoter activity in 293T cells expressing Jak1Spade or WT Jak1 cDNA. (F and G) Topical application of the JAK inhibitor was done on mice 3 times per week, from 4 to 12 weeks of age. Dermatitis incidence (F) and clinical ear score (G) for Jak1Spade/Spade mice treated with the JAK inhibitor in AOO or solvent alone. Each circle represents the mean ± SD of 8 mice per group. **P < 0.01, by Mann-Whitney U test. The average number of weeks to onset was 10.71 ± 1.25 for mice treated with inhibitor and 8.00 ± 0.76 for mice treated with solvent alone (P = 0.00018, by 2-tailed Student’s t test). (H) Frozen ear sections from WT and Jak1Spade/Spade mice 3 weeks after JAK inhibitor or solvent treatment were stained with anti–pY-JAK1 and Ki67 (both red) and K6 (green), and nuclei were counterstained with DAPI (blue). Scale bars: 20 μm.